Tigecycline, (4S,4aS,5aR,12aS)-4,7-Bis(dimethylamino)-9-[[[(1,1-dimethylethyl)amino]acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide, is a 9-t-butylglycylamido derivative of minocycline (Merck Index 14th Edition, monograph number 9432, CAS Registry Number 220620-09-7). Compared to other tetracycline antibiotics Tigecycline is more active against tetracycline-resistant strains and also more tolerable. Tigecycline possesses activity against bacterial isolates containing the two major determinants responsible for tetracycline-resistance: ribosomal protection and active efflux of the drug out of the bacterial cell. Furthermore Tigecycline possesses broad spectrum activity, e.g. it is active against gram-positive pathogens (e.g. methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci), gram-negative pathogens (e.g. Acinetobacter baumannii, Stenotrophomonas maltophilia) and anaerobic pathogens. At the moment Tigecycline is indicated for the treatment of complicated skin and soft-tissue infections and intra-abdominal infections. (P. J. Petersen et al., Antimicrob. Agents Chemoth. 1999; 43: 738-744. R. Patel et al., Diagnostic Microbiology and Infectious Disease 2000; 38: 177-179. H. W. Boucher et al., Antimicrob. Agents Chemoth. 44: 2225-2229. D. J. Biedenbach et al., Diagnostic Microbiology and Infectious Disease 2001; 40: 173-177. P. J. Petersen et al., Antimicrob. Agents Chemoth. 2002; 46: 2595-2601. D. Milatovic et al., Antimicrob. Agents Chemoth. 47: 400-404. T. Hirata et al., Antimicrob. Agents Chemoth. 2004; 48: 2179-2184. G. A. Pankey, Journal of Antimicrobial Chemotherapy 2005; 56: 470-480. R. Harris et al., P&T 2006; 31: 18-59.).
U.S. Pat. No. 5,675,030 claims a method of extracting Tigecycline dihydrochloride of unknown solid state.
WO 2005/056538, WO 2006/130418, WO 2006/130431, WO 2006/130500 and WO 2006/130501 disclose Tigecycline, acid addition salts of Tigecycline and processes of preparing the same as well. However, in literature no crystalline Tigecycline dihydrochloride or a method for its preparation is described.
Tigecycline is available on the market as lyophilized powder for injection, the originator is Wyeth. During the formulation process Tigecycline is first dissolved in water and then lyophilized. Therefore a crystalline form of Tigecycline or an alternative crystalline acid addition salt of Tigecycline should show high water solubility. The inventors of the present invention surprisingly found that crystalline form C of Tigecycline dihydrochloride clearly shows the highest water solubility compared with any of the crystalline forms of Tigecycline or Tigecycline hydrochloride.
Generally, crystalline solids have improved chemical and physical stability over the amorphous form and forms with low crystallinity, therefore crystalline Tigecycline dihydrochloride is more preferred than amorphous Tigecycline dihydrochloride. Thus there remains a need for crystalline Tigecycline dihydrochloride with high water solubility and suitable stability properties for the formulation of an anti-infective medicament.